R547

Catalog No.S2688

R547 is a potent ATP-competitive inhibitor of CDK1/2/4 with Ki of 2 nM/3 nM/1 nM. It is less potent to CDK7 and GSK3α/β, while inactive to other kinases. Phase 1.

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R547 Chemical Structure

R547 Chemical Structure
Molecular Weight: 441.45

Validation & Quality Control

Quality Control & MSDS

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  • R547 Mechanism

Product Description

Biological Activity

Description R547 is a potent ATP-competitive inhibitor of CDK1/2/4 with Ki of 2 nM/3 nM/1 nM. It is less potent to CDK7 and GSK3α/β, while inactive to other kinases. Phase 1.
Targets CDK4/CyclinD1 [1] CDK1/CyclinB [1] CDK2/CyclinE [1] PKA [1]

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IC50 1 nM(Ki) 2 nM(Ki) 3 nM(Ki) >5 μM(Ki)
In vitro R547 identified as a diaminopyrimidine compound, which is a potent and selective ATP-competitive CDK inhibitor. R547 effectively inhibits CDK1/cyclinB, CDK2/cyclinE, and CDK4/cyclinD1(Ki=1-3nM) and is inactive(Ki>5,000nM) against a panel of >120 unrelated kinases. R547 effectively inhibits the proliferation of tumor cell lines independent of multidrug resistant status, histologic type, retinoblastoma protein, or p53 status, with IC50s <0.60 μM. R547 reduces phosphorylation of the cellular retinoblastoma protein at specific CDK phosphorylation sites at the same concentrations that induced cell cycle arrest, suggesting a potential pharmaco dynamics marker for clinical use. R547 inhibits the proliferation of tumor cell lines and is active in all 19 cell lines tested irrespective of tissue of origin, multidrug resistance (MDR), p53, or retinoblastoma status. [1] R547 possessing both 5-and 6-fluoro substitution culminated in an Inhibitor with low, single-digit nanomolar potency against the CDKs(Ki=0.001,0.003,and 0.001 μM for CDK1,CDK2, and CDK4,respectively) and excellent cellular potency (IC50=0.08 μM,HCT116 cell line). [2]
In vivo R547 administered with oral and i.v. dosing in multiple established human tumor significantly inhibits tumor activity(P < 0.01). R547 administered orally at dose of 40 mg/kg daily in colon, lung, breast, prostate, and melanoma human tumor xenograft models shows significant TGI (79-99%). R547 is equally efficacious (TGI, 61-95%) when dosed with 40 mg/kg i.v. once weekly. These doses of R547 are not toxic and did not result in body weight loss. R547 does not show signs of overt toxicity during the course of the 3-week study and any gross pathology at necropsies done at the end of the studies. [1] R547 inhibits tumor growth up to 95% in the HCT116 human colorectal tumor xenograft model in nude mice . R547 causes significant TGI in all of the models tested when dosed orally and i.v. at or below the maximum tolerated dose. R547 inhibits phosphorylation of retinoblastoma protein in tumors at the efficacious exposures in tumor xenograft models, providing a pharmacodynamic biomarker for clinical use. R547 reported here suggests that this is a promising molecule for evaluation in the treatment of solid tumors. [2]
Features

Protocol(Only for Reference)

Kinase Assay:

[1]

Kinase Assays Enzyme reactions are initiated by adding recombinant histidine-tagged enzyme and retinoblastoma substrate to 384-well plates containing diluted test compounds. Final reaction conditions are such that the ATP concentration is 3× the respective enzyme Km for ATP in the presence of 25 mM HEPES (pH 7.0), 6.25 mM MgCl2, 1.5 mM DTT, 0.002% Tween 20, and 0.2 mg/mL bovine serum albumin (BSA). After a 25-minute incubation at 37 °C, reactions are terminated by addition of anti-phosphorylated retinoblastoma (Ser780) antibody. The phosphorylated retinoblastoma is analyzed by adding lance europium anti-rabbit IgG and anti-his- allophycocyanin, resulting in fluorescence resonance energy transfer between europium anti-rabbit and allophycocyanin, and quantified by fluorescence intensity ratio 665 nm/615 nm (excited at 340 nm). IC50s are calculated from net readings at 665 nm, normalized for europium readings at 615 nm. The kinase insert domain-containing receptor, fibroblast growth factor receptor, platelet-derived growth factor receptor, and epidermal growth factor receptor kinase assays are also homogeneous time-resolved fluorescence assays. Protein kinase A, protein kinase B, protein kinase Cα, protein kinase Cβ, FYN, extracellular signal-regulated kinase 2, p38, mitogen-activated protein kinase 2,serum/glucocorticoid-regulated kinase, and EPHB3 assays are conducted using an assay based on IMAP Technology that enables quantitation of kinase activity via preferential binding of phosphorylated fluorescent peptide substrates to immobilized metal beads. These reactions are carried out at ATP concentrations of 3× the Km for the respective enzyme. SRC, focal adhesion kinase, AURORA, glycogen synthase kinase (GSK) 3β, and insulin-like growth factor receptor kinase assays are fluorescence resonance energy transfer assays run at the Km for ATP. R547 is also evaluated for activity against 123 kinases at a single 10 μM concentration in the Upstate kinase selectivity screen and the IC50s determined in the Upstate IC50 Profiler Express for kinases identified as hits in the initial screen.

Animal Study:

[2]

Animal Models female nude mice bearing established HCT116 human colorectal xenografts with a mean starting volume of about 100 mm3
Formulation suspension 1% Klucel LF in water with 0.1% Tween 80
Dosages 25 ,50,75 mg/kg
Administration Orally three times per week on Monday, Wednesday, and Friday for 18days

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDog
Weight (kg)0.020.151.80.40.0810
Body Surface Area (m2)0.0070.0250.150.050.020.5
Km factor36128520
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Rodriguez A , et al. Mol Cancer Ther, 2006, 5(11), 2644-2658.

[2] Chu XJ, et al. J Med Chem, 2006, 49(22), 6549-6560.

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Chemical Information

Download R547 SDF
Molecular Weight (MW) 441.45
Formula

C18H21F2N5O4S

CAS No. 741713-40-6
Storage 3 years -20℃powder
2 years -80℃in solvent
Synonyms Ro 4584820
Solubility (25°C) * In vitro DMSO 60 mg/mL (135.91 mM)
Water <1 mg/mL
Ethanol <1 mg/mL
In vivo 1% hydroxyethyl cellulose+0.2% Tween 80 30 mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
Chemical Name (4-amino-2-(1-(methylsulfonyl)piperidin-4-ylamino)pyrimidin-5-yl)(2,3-difluoro-6-methoxyphenyl)methanone

Tech Support

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
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